White adipose tissue (WAT) transplantation, although widely used in humans, has been done for cosmetic and reconstructive purposes only. Accumulating evidence indicates, however, that WAT is an ...important endocrine organ and, therefore, WAT transplantation may become valuable as a replacement therapy for a number of hereditary human diseases. Because the most readily available source for such transplantations would be allogeneic tissue, the mechanisms involved in the rejection of WAT allograft should be explored. We have established a model in which leptin-producing allogeneic WAT is transplanted into leptin-deficient ob/ob mice. Because ob/ob mice are obese, hyperphagic, and hypothermic, WAT allograft function is monitored as the reversal of this leptin-deficient phenotype. Here we report that allografted WAT is primarily nonfunctional. However, when WAT is transplanted into immunodeficient (Rag1–/–) ob/ob mice, or into ob/ob mice depleted of T cells by anti-CD3 antibody, a long-term graft survival is achieved as indicated by the reversal of hyperphagia, weight loss, and normalization of body temperature. The symptoms of leptin deficiency rapidly recur when normal spleen cells of the recipient type are injected, or when the antibody treatment is terminated. In contrast, selective depletion of either CD4+ or CD8+ cells alone does not prevent WAT allograft rejection. Similarly, WAT allografts that do not express MHC class I or class II molecules are rapidly rejected, suggesting that both CD4+ and CD8+ T cells may independently mediate WAT allograft rejection.
We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia ...(FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.
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•Structural variants were called in the genomes of non-Alzheimer’s dementias•Discovery of TPCN1 as a novel risk locus for Lewy body dementia•Structural variants at C9orf72 and MAPT were present in frontotemporal dementia•Gene-set analyses identified likely pathogenic rare structural variants
This article from Kaivola, Chia, and Ding et al. describes the identification, characterization, and analysis of structural variants in genome data from patients with the non-Alzheimer’s dementias Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Surgery for Severe Ischemic Mitral Regurgitation Kara, Ibrahim; Koksal, Cengiz; Kahveci, Gökhan ...
New England journal of medicine/The New England journal of medicine,
05/2016, Volume:
374, Issue:
20
Journal Article
Peer reviewed
Open access
To the Editor:
Goldstein et al. (Jan. 28 issue)
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report on 2-year outcomes of the Cardiothoracic Surgical Trials Network trial of surgical treatment of severe ischemic mitral regurgitation. The aim ...of restrictive mitral annuloplasty in patients with this condition is to eliminate mitral regurgitation and provide an adequate surface for coaptation. Proper patient selection is therefore the key to avoiding a risky repeat operation.
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Certain echocardiographic criteria (such as coaptation depth, tethering area, left ventricular end-diastolic and end-systolic diameters, posterior leaflet angle, and annular dilatation) and clinical criteria play an important role in determining which patients should undergo an . . .
Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer's disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To ...identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case-control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls. We estimated odds ratios and 95% confidence intervals for the association of Lewy body dementia risk with 1017 prescription drugs overall and separately for the three major racial groups (Black, Hispanic and White Americans). We identified significantly reduced Lewy body dementia risk associated with drugs used to treat cardiovascular diseases (anti-hypertensives: odds ratio = 0.72, 95% confidence interval = 0.70-0.74,
-value = 0; cholesterol-lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83-0.87,
-value = 0; anti-diabetics: odds ratio = 0.83, 95% confidence interval = 0.62-0.72,
-value = 0). Notably, anti-diabetic medications were associated with a larger risk reduction among Black Lewy body dementia patients compared with other racial groups (Black: odds ratio = 0.67, 95% confidence interval = 0.62-0.72,
-value = 0; Hispanic: odds ratio = 0.86, 95% = 0.80-0.92,
-value = 5.16 × 10
; White: odds ratio = 0.85, 95% confidence interval = 0.82-0.88,
-value = 0). To independently confirm the epidemiological findings, we looked for evidence of genetic overlap between Lewy body dementia and cardiovascular traits using whole-genome sequence data generated for 2591 Lewy body dementia patients and 4027 controls. Bivariate mixed modelling identified shared genetic risk between Lewy body dementia and low-density lipoprotein cholesterol levels, Type 2 diabetes and hypertension. By combining epidemiological and genomic data, we demonstrated that drugs treating cardiovascular diseases are associated with reduced Lewy body dementia risk, and these associations varied across racial groups. Future randomized clinical trials need to confirm our findings, but our data suggest that assiduous management of cardiovascular diseases may be beneficial in this understudied form of dementia.
The effect of comorbid avoidant personality disorder (APD) on response to exposure-based treatment for social phobia was examined in a sample of 48 outpatients with generalized social phobia. ...Diagnoses were based on the Structured Clinical Interview for DSM-III-R. At pretest, clients with APD were more severely impaired on all self-report measures and had a higher frequency of comorbid diagnoses than those without the disorder. Although clients with APD improved significantly with treatment, they continued to report more severe impairment on all outcome measures at posttest and 3-month follow-up as compared to those without APD. Depression may in part explain the poorer rate of improvement during treatment of those with APD.
The impact of concurrent Axis I and Axis II disorder diagnoses on the efficacy of psychotherapy in a clinical setting for panic disorder with agoraphobia was studied in a sample of 51 agoraphobic ...outpatients. Diagnoses were based on the Structured Clinical Interview for DSM-III-R. The effects of secondary major depression, dysthymia, generalized anxiety disorder, and avoidant personality disorder were examined via multiple regression analyses. Major depression was associated with less improvement on phobic behavior at 6-month follow-up, whereas dysthymia and avoidant personality disorder predicted less reduction in the frequency of panic attacks at posttest and follow-up, respectively. There was little evidence that generalized anxiety was associated with poorer outcome in this sample. Limitations to the internal validity of the study include uncontrolled use of medication and naturalistic treatment during the follow-up period.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
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